A kind of preparation method of bromfenac sodium sesquihydrate

A technology of sesquihydrate and bromfenac sodium, which is applied in the preparation of organic compounds, cyanide reaction preparation, chemical instruments and methods, etc., can solve the risk of inability to obtain bromfenac sodium sesquihydrate and organic solvent residues Large, unfavorable industrial production and other problems, to achieve the effect of simple and easy preparation method, lower production cost, and less discharge of three wastes

Active Publication Date: 2016-03-30
GUANGDONG ZHONGSHENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] At present, bromfenac sodium anhydrate can only be obtained by crystallization or recrystallization of bromfenac sodium using environmentally friendly solvents, namely water and organic alcohols, but bromfenac sodium sesquihydrate cannot be obtained
However, the preparation of bromfenac sodium sesquihydrate in the prior art requires the use of ether organic solvents such as ethylene glycol dimethyl ether, which has poor environmental benefits and a large risk of organic solvent residues, which is not conducive to industrial production

Method used

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  • A kind of preparation method of bromfenac sodium sesquihydrate
  • A kind of preparation method of bromfenac sodium sesquihydrate
  • A kind of preparation method of bromfenac sodium sesquihydrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] In a 5L reaction flask, add 500g of bromfenac sodium anhydrate and 0.75g of sodium sulfite to a mixed solvent of 500mL of water and 500mL of ethanol. After heating to dissolve, add acetic acid to adjust the pH to 9.0, then add 1500mL of ethanol, and cool to 30℃, add 15g bromfenac sodium sesquihydrate as seed crystals, stir well, cool to 5℃, stand for 1h to crystallize, collect the crystals by centrifugation, and vacuum dry at 50℃, -0.095MPa~-0.090MPa Within 15 hours, 341.5 g of bromfenac sodium sesquihydrate was obtained, the mass yield was 68.3%, the purity was 99.69%, the single largest impurity content was 0.054%, and the moisture content was 6.97%.

[0045] The HPLC diagram of the related substances of bromfenac sodium sesquihydrate prepared in this example is as follows figure 1 Shown.

[0046] The infrared spectrum of bromfenac sodium sesquihydrate prepared in this example is as follows figure 2 Shown.

[0047] The X-ray powder diffraction spectrum of bromfenac sodium...

Embodiment 2

[0051] In a 1L reaction flask, add 100g of bromfenac sodium anhydrate and 0.20g of sodium thiosulfate to a mixed solvent of 100mL of water and 100mL of methanol. After heating to dissolve, add acetic acid to adjust the pH to 10.0, and then add 250mL of methanol , Cool to 35℃, add 3.0g bromfenac sodium monohydrate as seed crystals, stir evenly, cool to 15℃, stir and crystallize for 2h, centrifuge to collect crystals, at 47℃, -0.095MPa~-0.090MPa After vacuum drying for 14 hours, 67.2 g of bromfenac sodium sesquihydrate was obtained, the mass yield was 67.2%, the purity was 99.67%, the single largest impurity content was 0.073%, and the moisture content was 7.04%.

Embodiment 3

[0053] In a 1L reaction flask, add 100g of bromfenac sodium monohydrate and 0.10g of sodium thiosulfate to a mixed solvent of 100mL of water and 100mL of isopropanol. After heating to dissolve, add acetic acid to adjust the pH to 8.0, and then add 300mL isopropanol, cool to 32℃, add 1.0g bromfenac sodium monohydrate and 1.0g bromfenac sodium sesquihydrate as seed crystals, after stirring uniformly, cool to 0℃, stir and crystallize for 1h, centrifuge The crystals were collected and dried in vacuum at 47°C and -0.095MPa~-0.090MPa for 16 hours to obtain 65.8g of bromfenac sodium sesquihydrate, with a mass yield of 65.8%, a purity of 99.75%, and a single maximum impurity content of 0.048 %, the moisture content is 6.49%.

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Abstract

The invention aims at providing a preparation method of bromfenac sodium sesquihydrate. The preparation method comprises the following steps: (1) adding bromfenac sodium and an antioxidant into a mixed solvent of water and an organic alcohol, heating, dissolving and adding a pH adjustor to adjust the pH to 7.0-10.5; (2) adding an anti-solvent into a solution obtained in the step (1), cooling the solution to 30 DEG C to 35 DEG C, adding bromfenac sodium monohydrate, bromfenac sodium sesquihydrate or a mixture thereof as a seed crystal, and stirring; and (3) cooling, crystallizing, collecting crystals and drying to obtain the bromfenac sodium sesquihydrate. The preparation method avoids use of ether agents and is mild in reaction condition and good in environmental benefit. The prepared bromfenac sodium sesquihydrate is high in purity.

Description

Technical field [0001] The invention belongs to the technical field of pharmacy, and specifically relates to a preparation method of bromfenac sodium sesquihydrate. Background technique [0002] The chemical name of bromfenac sodium is 2-amino-3-(4-bromobenzoyl)phenylacetate, which is one of the derivatives of 2-amino-3-benzoylphenylacetic acid, and its structure is similar to that of ketoprofen. Similar to diclofenac, it can inhibit the synthesis of cyclooxygenase-mediated prostaglandin inflammatory mediators. It is the most effective cyclooxygenase inhibitor. It has a powerful anti-inflammatory and analgesic effect. Its strength is the same as that of other non-steroidal anti-inflammatory drugs. 10 times. [0003] The data released by the Center for Drug Evaluation and Research (CDER) under the US FDA show that the medicinal crystal form of bromfenac sodium (Application Number 21-664) is a sesquihydrate, that is, crystal form I. [0004] Example 74 in patent document EP0221753 an...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/42C07C227/42
Inventor 谭珍友程志伟黄爱君贺忠玉
Owner GUANGDONG ZHONGSHENG PHARMA
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